Arylacetic acid derivatives

ABSTRACT

Arylacetic acid derivatives of the formula ##STR1## with R 1 , R 2  and R 3  specifically defined and which are useful as antirheumatic and antiinflammatory pharmaceuticals are practiced by catalytic hydrogenation of new compounds of the formula ##STR2## in which R and R 10  are also specifically defined. The method of making the latter compound is also set forth.

The present invention relates to a new process for the preparation ofarylacetic acid derivatives of the formula I ##STR3## wherein R¹ ishydrogen, methyl or ethyl;

R² is hydrogen, fluorine or an alkyl having 1 to 4 carbon atoms;

R³ is hydrogen, phenyl, alkoxy having 1 to 6 carbon atoms, phenoxy orunsubstituted or substituted benzoyl or thenoyl; or

R² and R³ together with the phenyl group they are attached to representa naphthyl group which can be substituted with one or more alkyl and/oralkoxy groups having 1 to 4 carbon atoms.

Compounds of the formula I, wherein R¹, R² and R³ are prepared accordingto the invention starting from compounds of the formula VIII ##STR4##wherein R is vinyl or carboxyl;

R¹⁰ is phenylaminocarbonyl, 1-phenyl-5-tetrazolyl, 2-benzoxyazolyl, an--SO₂ OMe group, wherein Me is a metal atom, preferably sodium orpotassium, or an --SO₂ R⁶ group, wherein

R⁶ is alkyl having 1 to 4 carbon atoms, 4-methylphenyl, amino,acylamino, alkoxycarbonylamino having 1 to 4 carbon atoms in the alkylmoiety or an R⁷ --N═C--NH--R⁷ group, wherein

R⁷ is alkyl having 1 to 4 carbon atoms, cycloalkyl having 5 or 6 carbonatoms or tolyl

and R¹, R² and R³ have the meanings defined above.

Compounds of the formula VIII are new, and are also within the scope ofthis invention.

According to the invention compounds of the general formula I, whereinR¹, R² and R³ have the meanings defined above, may be prepared bysubjecting new arylacetic acid derivatives of the formula VIII, whereinR¹, R², R³ and R¹⁰ have the meanings defined above and R is carboxyl, tocatalytic hydrogenation.

It is well known that many of the substituted arylacetic acidderivatives of the formula I possess valuable antirheumatic andantiinflammatory properties and have small side-effects. These compoundsare widely used in human therapy. They are for example described in theU.S. Pat. No. 3,600,437; German Pat. No. 1,941,625; Belgian Pat. Nos.621,225 and 787,417; British Pat. Nos. 971,700 and 1,132,318; FrenchPat. Nos. 1,545,270 and 1,549,728 as well as in the Hungarian patentapplication RO-687.

In the majority of the methods known for the preparation of thecompounds of the formula I compounds of the formula XI ##STR5## whereinR¹¹ is carboxyl, carbalkoxy, optionally substituted carboxylic acidamido or nitrile,

and R² and R³ are as defined, are reacted with alkylating agents of theformula XII

    R.sup.1 -X                                                 (XII)

wherein

R¹ has the same meaning as defined above and

X is halogen or a CH₃ C₆ H₄ N═N--NH group, and, if desired, a compoundobtained, in which R¹¹ is other than carboxyl, is converted into acorresponding compound of the formula I in a manner known per se. Thereaction is illustrated on the following Chart A ##STR6## and isdescribed in the German Pat. Nos. 1,668,648 and 1,941,625; U.S. Pat.Nos. 3,600,437 and 3,755,427, Belgian Pat. No. 752,627 and Hollandpatent application No. 74,06897.

A common feature of these processes is that their critical step is theformation of a C-C bond between the alkylating agent and the carbon atomadjacent to the carboxyl group. The reaction can either be performedwith very moderate yields or yields the desired product through moreintermediates, which are difficult to purify, involving complicatedtechnology.

According to other methods an α-substituted alkane-carboxylic acid groupis introduced into a suitably substituted aryl ring by electrophilicsubstitution, and the product obtained is converted into a correspondingfree acid. The reaction is illustrated on Chart B below: ##STR7##wherein R¹, R², R²² and X have the above-defined meanings. Similarreactions are described in the British Pat. No. 971,700 and in theBelgian Pat. Nos. 621,225 and 748,534.

These processes can only restrictedly be used, partly due to a potentialdeactivating effect of certain substituents, e.g. keto group, and partlybecause of their unsatisfactory selectivity.

Another group of known processes relates to the formation of a branch inthe α-position of the alkanecarboxylic acid group by isomerization, asshown on Chart C: ##STR8## According to U.S. Pat. No. 3,803,245 thallicnitrate is used for this purpose. This method, however, because of thetoxicity of thallium can be industrially used only very carefully, underspecial precautions.

It has now surprisingly been found that compounds of the formula I,wherein R¹, R² and R³ are as defined above, can be prepared very easilyby hydrogenating compounds of the formula VIII, in which R represents acarboxyl group, and R¹, R², R³ and R¹⁰ have the above-identifiedmeanings.

In the compounds prepared and used according to the invention the terms"alkyl and alkoxy groups" refer to straight or branched chainhydrocarbon groups, such as methyl, ethyl, isopropyl, n-butyl, tertiarybutyl and methoxy, ethoxy and isopropoxy.

In the definition of X the term "halogen" preferably representschlorine, bromine or iodine.

In the definition of R⁶ the term "acylamino" preferably indicates anoptionally substituted benzoyl or an alkanoyl amino group having 1 to 5carbon atoms, e.g. formyl, acetyl, and propionyl amino.

In the definition of R³ and R⁶ the substituents may be selected from thefollowing groups: amino, nitro, C₁₋₄ -alkylamino, C₁₋₄ -alkyl-C₁₋₄-alkoxy, and halogen.

In the definition of Y the "halogen" is preferably chlorine or bromine.

According to a preferred embodiment of the invention arylacetic acidderivatives of the formula I are prepared by carrying out catalytichydrogenation in water or in an organic solvent, preferably at atemperature between 20° to 90° C., under a pressure of 1 to 3 atm.

As organic solvents preferably alcohols, more particularly methanol orethanol; benzene; dioxane; ethylacetate; dimethyl formamide or organicacids, more particularly acetic acid can be used. Reaction is preferablyaccomplished in the presence of an inorganic base, e.g. an alkali metalhydroxide, preferably sodium or potassium hydroxide; alkali metalalcoholate, preferably sodium methylate or sodium ethylate; or in thepresence of an organic base, e.g. triethyl amine.

The compounds of the formula VIII are new as noted above. The presentinvention concerns also these compounds as well as a process for thepreparation of same.

According to the invention compounds of the formula VIII, wherein R,R¹⁰, R¹, R² and R³ are as defined hereinbefore, are prepared by reactinghydroxyl derivatives of the formula V ##STR9## wherein R¹, R² and R³ areas defined above, (a) with compounds of the formula VI

    R.sup.5 -Y                                                 VI

wherein

R⁵ is 1-phenyl-5-tetrazolyl, 2-benzoxazolyl or an --SO₂ R⁶ group, inwhich

R⁶ has been defined above, and Y represents halogen; or

(b) with phenylisocyanate; or

(c) with compounds of the formula IX

    R.sup.7 --N═C═N--R.sup.7                           IX

wherein R⁷ has been defined above; or

(d) with compounds of the formula X ##STR10## wherein R⁸ is alkyl havingfrom 1 to 4 carbon atoms, and

R⁹ is alkyl having from 1 to 4 carbon atoms or phenyl; or

(e) with a pyridine-sulphur trioxide complex, and, if desired oxidizinga compound of the formula VIII obtained, in which R is a vinyl groupinto another compound of the formula VIII, in which R represents acarboxyl group.

A narrower group of the compounds of the formula VIII, more particularlycompounds of the formula XIII ##STR11## wherein R¹, R² and R³ and R⁵ areas defined hereinbefore, are prepared according to process variant (a)of the invention by reacting hydroxyaryl derivatives of the formula V,wherein R¹, R² and R³ are as defined above, with methanesulphonylchloride, p-toluene sulphonylchloride, sulphaminic acidchloride, N-benzoyl-sulphaminic acid chloride or N-methoxy-sulphaminicacid chloride, in water and/or in organic solvents. This reaction ispreferably carried out at a temperature of 0° C. to 40° C.

As an organic solvent pyridine, acetone, methylene chloride or benzeneis preferably used and the reaction is preferably carried out in thepresence of an inorganic base, e.g. alkali or alkali earth metalhydroxide or carbonate; or of an organic base, e.g. triethylamine.

According to a preferred embodiment of process variant (b) thosecompounds of the formula VIII, which can be encompassed by the formulaXIV ##STR12## wherein R¹, R² and R³ are as defined above, can beprepared by reacting a hydroxyaryl derivative of the general formula V,in which R¹, R² and R³ have the meanings defined above, with phenylisocyanate, optionally in the presence of an organic solvent, preferablypetroleum ether. The reaction is preferably carried out at a temperatureof 20° C. to 100° C., in the presence of an alkaline catalyst,preferably pyridine.

According to process variant (c) those compounds of the formula VIII,which can be encompassed by the formula XV ##STR13## wherein R¹, R², R³and R⁷ are as hereinbefore defined, are prepared by reacting ahydroxyaryl derivative of the formula V, wherein R¹, R² and R³ have themeanings as defined above, with an excess amount of dicyclohexylcarbodiimide or di-p-tolyl-carbodiimide, in the absence of solvent,preferably at a temperature of 20° C. to 100° C.

According to process variant (d) those compounds of the formula VIII,which are encompassed by the formula V ##STR14## in which R¹, R², R³ andMe are as hereinbefore defined, are prepared by reacting a hydroxyarylderivative of the formula V, wherein R¹, R² and R³ are as defined with asulphur trioxide complex of N,N-dimethylaniline, N,N-diethyl-aniline ortrimethyl-aniline in an organic solvent, preferably in carbon disulphideor benzene, at a temperature of -10° C. to +40° C., and subsequentlytreating the reaction mixture with an aqueous solution of an inorganicbase. The reaction is preferably carried out in the presence of anexcess amount of a base (for example aqueous sodium or potassiumhydroxide solution).

According to process variant (e) those compounds of the formula VIII,which are encompassed by the formula XVI are prepared by reacting ahydroxyaryl derivative of the formula V with pyridine-sulphur trioxidecomplex, in an organic solvent, preferably in carbon disulphide orbenzene, at a temperature between -10° C. and +40° C., and treating thereaction mixture obtained with an aqueous solution of an inorganic base.The reaction is performed in the presence of an excess amount of aqueoussodium or potassium hydroxide solution.

The compounds of the formula VIII, in which R represents a vinyl groupcan be converted into corresponding compounds of the formula VIII, inwhich R is carboxyl by oxidation. The oxidation can, for example, becarried out with potassium permanganate, in the presence of an organicsolvent, preferably at a temperature of 0° C. to 40° C. As an oxidizingagent an alkali metal periodate, preferably sodium or potassiumperiodate can also be successfully used. Suitable solvents are waterand/or organic solvents, preferably tert.-amylalcohol, benzene, pentane,methylene chloride, acetone. According to an especially preferredembodiment of the process the process is carried out in the presence ofa phase-transforming catalyst and acetic acid. As a catalyst preferablytetrabutyl ammoniumchloride, tetrabutyl-ammoniumbromide,triethyl-benzyl-ammoniumchloride, tricaprilyl-methyl-ammoniumchloride,trioctyl-methyl-ammoniumchloride orbenzyl-hexadecyl-dimethyl-ammoniumchloride or crown ether, preferably18-crown-6 or dicyclohexyl-18-crown-6 can be used.

Of the compounds of the formula V which are used as starting compoundsin the preparation of new compounds of the formula VIII, the followingare new:

3-isobutyl-6-allyl-phenol,

3-isobutyl-6-(1-methyl-allyl)-phenol;

4-phenoxy-2-(1-methyl-allyl)-phenol;

4-phenoxy-2-allyl-phenol,

2-allyl-6-methoxy-naphthol,

2-(1-methyl-allyl)-naphthol, and

4-benzoyl-2-(1-methyl-allyl)-phenol.

The compounds of the formula V can be prepared in a manner known per se,by reacting compounds of the formula II ##STR15## wherein R² and R³ areas defined above, with compounds of the formula III

    R.sup.1 --CH═CH--CH.sub.2 --X                          (III)

and subjecting the obtained compounds of the formula IV ##STR16## tothermal isomerization.

The following compounds of the formula IV are new:

2-fluoro-5-allyloxy-diphenyl,

2-fluoro-5-crotyloxy-diphenyl,

(3-isobutylphenyl)-allyl-ether,

(3-isobutyl-phenyl)-crotyl-ether,

4-allyloxy-diphenylether,

4-crotyloxy-diphenylether,

4-crotyloxy-benzophenone,

1-allyloxy-6-methoxy-naphthalene, and

1-crotyloxy-6-methoxy-naphthalene.

The aryloxy derivatives of the formula IV are preferably prepared inwater and/or in an organic solvent, preferably acetone, dimethylformamide, ether, in the presence of a base, preferably potassiumcarbonate or sodium carbonate, at a temperature of 20° C. to 100° C.

The thermal isomerization of the compounds of the formula IV ispreferably effected at 150° C. to 260° C., in the absence of solvent orin an organic solvent, preferably N,N-dimethylaniline,N,N-diethylaniline, dimethyl formamide or diphenyl ether.

According to the process provided by this invention compounds of theformula I can be prepared starting from compounds of the formula II inan entirely new manner, through new intermediates as illustrated onChart D. ##STR17## The process according to the invention isconsiderably easier to carry out also on industrial scale than theprocesses known in the art.

Further details of the invention are illustrated by the followingillustrative and non-limiting Examples.

EXAMPLE 1

To a solution of 19.8 g. of 4-hydroxy-benzophenone in 100 ml. of dryacetone 18.3 g. of crotyl bromide and 14 g. of anhydrous potassiumcarbonate are added. The reaction mixture is boiled for 4 hours withstirring and acetone is distilled off. The residue is treated with waterand the separated oil is taken up in ether. The ethereal solution iswashed with a dilute aqueous sodium hydroxide solution and subsequentlywith water, and is then dried over sodium sulphate. Upon distilling offof the ether 4-crotyloxy-benzophenone is obtained as a pale yellow oil,which crystallizes in one to two days to afford a product melting at 36°C.

EXAMPLE 2

A solution of 5 g. of 4-crotyloxy-benzophenone in 15 ml. of diphenylether is boiled for one hour. It is allowed to cool and is diluted withpetroleum ether. The solution obtained is extracted with a 5 N sodiumhydroxide solution. The alkaline phase is acidified with a diluteaqueous hydrochloric acid solution, the precipitated crystals arefiltered off with suction and recrystallized from cyclohexane to give4-benzoyl-2-(1-methyl)-allyl-phenol, melting at 111° C. to 113° C.

EXAMPLE 3

To a solution of 104 ml. of o-cresol in 200 ml. of acetone a solution of40.8 g of sodium hydroxide in 160 ml. of water is added. To the reactionmixture 104 ml. of crotyl bromide are added dropwise, with stirring,under cooling with ice-water. Stirring is continued for a further 2hours, whereupon the mixture is brought to the boil and boiled for anadditional hour. After cooling the organic phase is separated, theaqueous phase is shaken with two 50-ml. portions of petroleum ether. Thecombined organic phases are shaken with eight 100-ml. portions of a 30%aqueous sodium hydroxide solution and washed to neutral with water. Uponthe distilling off of petroleum ether o-cresol-crotyl ether is obtainedas a yellow, oily residue.

o-cresol-crotyl ether obtained is refluxed until the boiling pointarises to 210° C. (about 4 hours). After cooling 160 ml. of a 20%aqueous potassium hydroxide solution are added and the reaction mixtureis shaken with three 50-ml. portions of petroleum ether. The aqueoussolution is acidified with a concentrated hydrochloric acid solution.The separated oil is taken up in ether, the ethereal solution is washedto neutral with water and dried over sodium sulphate. Ether is distilledoff and the remaining oil is subjected to distillation in vacuo fo yield2-methyl-6-(1-methyl)-allyl-phenol. n_(D) ²⁵ =1.5315.

EXAMPLE 4

8.62 g. of 4-phenoxy-phenyl-crotyl ether (prepared according to DOS2,304,962) in 30 ml. of diphenyl ether are refluxed for one hour at 260°C. The reaction mixture is cooled to room temperature, diluted with 30ml. of petroleum ether and shaken with two 25-ml. portions ofClaisen-alkali. The alkaline phase is acidified with a concentratedaqueous hydrochloric acid solution and shaken with three 30-ml. portionsof ether. The combined ethereal phases are dried over sodium sulphateand evaporated to give 2-(1-methyl-allyl)-4-phenoxy-phenol.

EXAMPLE 5

To a solution of 48.7 g. of 2-allyl-phenol in 176 ml. of dry pyridine 34ml. (51,3 g.) of mesyl chloride are added dropwise, with stirring, undercooling. The reaction mixture is allowed to stand for 2 hours and isthen poured on a mixture of concentrated hydrochloric acid and ice. Theprecipitated oil is taken up in ether, the ethereal solution is washedwith a 2 N sodium hydroxide solution and subsequently with water, and isdried over sodium sulphate. Ether is distilled off to give 69.4 g. of2-allyl-phenol mesylester. n_(D) ²⁵ =1.5191.

EXAMPLE 6

To a cooled solution of 14.7 g. of 2-(1-methyl)-allyl-phenol in 50 ml.of dry pyridine 14.5 g. of mesyl chloride are added dropwise, withstirring. The reaction mixture is allowed to stand overnight, whereuponit is poured onto a mixture of concentrated hydrochloric acid and ice.The separated oil is taken up in ether. The ethereal solution is washedwith a 2 N sodium hydroxide solution and subsequently with water, and isthen dried over sodium sulphate. Ether is distilled off to give 20 g. of2-(1-methyl)-allyl-phenol mesylester. n_(D) ²⁵ =1.5197.

EXAMPLE 7

Following the procedure described in Example 6 but replacing2-(1-methyl-allyl-phenol by 18.4 g. of 2-allyl-1-naphthol 20.5 g. of2-allyl-1-naphthol mesylester are obtained as a slowly solidifying oil.The oily product crystallizes in 1 to 2 days and the melting point ofthe crystals obtained amounts of 45° C.

EXAMPLE 8

To a cooled solution of 33.8 g. of 2-allyl-phenol in 125 ml. of drypyridine 47.5 g. of p-toluene-sulphonic acid chloride are added in smallportions, with stirring. The mixture is stirred for three hourswhereupon it is poured onto the mixture of concentrated hydrochloricacid and ice. Then the procedure described in Example 6 is followed.2-allyl-phenol tosylester is obtained. n_(D) ²⁵ =1.5543.

EXAMPLE 9

A mixture of 13.5 g. of 2-allyl-phenol, 13.1 g. of phenylisocyanate and0.5 g. of pyridine is kept at 100° C. for five minutes. Petroleum etheris added whereupon the precipitated crystals are filtered off withsuction and washed with petroleum ether to give2-allyl-phenol-phenylurethane, melting at 108° C. to 109° C.

EXAMPLE 10

Following the procedure described in Example 9 but starting from 18.4 g.of 2-allyl-1-naphthol, 13.1 g. of phenyl-isocyanate and 0.5 ml. ofpyridine and recrystallizing the product obtained from carbontetrachloride 2-allyl-1-naphthol-phenyl-urethane is prepared, melting at141° C. to 142° C.

EXAMPLE 11

Following the procedure described in Example 9 but starting from 3.4 g.of 2-(1-methyl)-allyl-phenol. 3.3 g. of phenyl-isocyanate and 0.1 ml. ofpyridine 2-(1-methyl)-allyl-phenol-phenyl-urethane is obtained, meltingat 92° C. to 94° C.

EXAMPLE 12

Following the procedure described in Example 9 but starting from 8.4 g.of 2-(1-methyl)-allyl-1-naphthol, 8.7 g. of phenyl-isocyanate and 0.2ml. of pyridine 2-(1-methyl)-allyl-1-naphthol-phenyl-urethane isobtained, melting at 138° C. to 142° C.

EXAMPLE 13

To a solution of 22 g. of 2-methyl-6-allyl-phenol [J. Org. Chem. 30,1032 (1965)] in 90 ml. of dry pyridine 24.6 g. of methanesulphonic acidchloride are added dropwise, with stirring, under cooling withice-water. The reaction mixture is allowed to stand at room temperatureovernight, and the reaction mixture containing crystals is poured onto amixture of 50 ml. of concentrated hydrochloric acid and 150 g. of ice.The oily phase is separated and the aqueous phase is extracted with two100-ml. portions of ether. The ethereal solution is combined with theoil, it is shaken with two 100-ml. portions of a 1:1 mixture ofhydrochloric acid and water, then washed to neutral with water and driedover sodium sulphate. Ether is distilled off and 2-methyl-6-allyl-phenolmesylester is obtained as a yellow oil. n_(D) ²⁵ =1.5252.

EXAMPLE 14

To a solution of 4.28 g. of 3-(1-methyl)-allyl-4-hydroxy-benzophenone in20 ml. of dry pyridine 2.2 g. of methane-sulphonic acid chloride areadded, and the reaction mixture is heated on a water-bath for fivehours. The reaction mixture is cooled and is poured on the mixture of 10ml. of concentrated hydrochloric acid and 100 g. of ice. The oily phaseis shaken with three 50-ml. portions of ether. The combined etherealextracts are shaken with three 20-ml. portions of 2 N hydrochloric acid,washed to neutral with water, shaken with two 20-ml. portions of a 2 Nsodium hydroxide solution, washed with water again and finally driedover sodium sulphate. Evaporation of the product yields3-(1-methyl)-allyl-4-mesyloxy-benzophenone as a yellow oil. n_(D) ²²=1.5732.

EXAMPLE 15

To a solution of 14.8 g. of 2-allyl-4-methyl-phenol [J. Am. Chem. Soc.80, 3271 (1958)] in 50 ml. of dry pyridine 14 g. of methane-sulphonicacid chloride are added dropwise, with stirring, under cooling withice-water. Furtheron the procedure described in Example 13 is followed.Distilling off the ether 2-allyl-4-methyl phenolmesylester obtained as ayellow oil.

EXAMPLE 16

To a solution of 16.2 g. of 2-(1-methyl)-allyl-4-methyl-phenol [Helv.45, 1943 (1962)] in 60 ml. of dry pyridine 18.43 g. of methanesulphonicacid chloride are added dropwise, with stirring, under cooling withice-water. Further on following the procedure described in Example 13and distilling off the ether 2-(1-methyl)-allyl-4-methyl-phenolmesylester is obtained as a yellow oil. n_(D) ²⁸ =1.5053.

EXAMPLE 17

To a solution of 32.44 g. of 2-methyl-6-(1-methyl)-allyl-phenol in 120ml. of dry pyridine 33.2 g. of methanesulphonic acid chloride are addeddropwise. with stirring, under cooling with ice-water. Further onfollowing the procedure described in Example 13 and distilling off ether2-methyl-6-(1-methyl)-allyl-phenol mesylester is obtained, which isdistilled in vacuo. Boiling point: 187° C. to 190° C./15 mmHg.; n_(D) ²¹=1.5283.

EXAMPLE 18

7.17 g. of 2-(1-methyl-allyl)-4-phenoxy-phenol are dissolved in 30 ml.of pyridine and 3.41 g. of mesyl chloride are added dropwise, withcooling. The reaction mixture is allowed to stand in a refrigeratorovernight, and is then poured onto a mixture of ice and 12 ml. ofconcentrated hydrochloric acid. The oily phase is shaken with three20-ml. portions of benzene. From the combined benzene fractionsunmesylated phenyl derivative is eliminated with two 20-ml. portions ofClaisen-alkali, and the organic phase is washed to alkaline-free. Thebenzene solution is dried over sodium sulphate and is evaporated. Thus2-(1-methyl-allyl)-4-phenoxy-phenyl-mesyl ester is obtained. n_(D) ²²=1.5565.

EXAMPLE 19

2 g. of 2-allyl-4-phenoxy-phenol are dissolved in 10 ml. of pyridine andto the cooled solution 1 g. of mesyl chloride is added dropwise. Thereaction mixture is allowed to stand overnight and is then poured onto amixture of ice and 5 ml. of concentrated hydrochloric acid. Theseparated oil is eliminated by extraction with three 20-ml. portions ofether. The combined ethereal solutions are shaken with two 10-ml.portions of 1 N sodium hydroxide, whereupon it is washed to neutral withwater. The ethereal solution is dried over sodium sulphate. Evaporationof the product affords 2-allyl-4-phenoxy-phenyl mesylester.

EXAMPLE 20

To a solution of 7.7 g. of 3-allyl-4-hydroxy-benzophenone [J. Am. Chem.Soc. 80, 3271 (1958)] in 43 ml. of dry pyridine 4.46 g. ofmethanesulphonic acid chloride are added dropwise, with stirring, undercooling with ice-water. Further on the procedure described in Example 13is followed. After distilling off ether 3-allyl-4-mesyloxy-benzophenoneis obtained as a yellowish brown oil.

EXAMPLE 21

To a solution of 19.8 g. of potassium permanganate in 1500 ml. ofacetone a solution of 5.3 g. of 2-allyl-phenol mesylester in 10 ml. ofacetone is added dropwise, with stirring, under cooling. The reactionmixture is allowed to stand overnight, and thereafter is acidified witha 5 N sulphuric acid solution and filtered. The filtrate is evaporatedin vacuo. The crystalline residue is admixed with a sodiumhydrogencarbonate solution, filtered and the filtrate is acidified witha 5 N hydrochloric acid solution. The precipitated crystals are filteredoff with suction to give 2-mesyloxy-phenyl-acetic acid, melting at 110°C. After recrystallization from a 50% ethanol solution the melting pointamounts to 125° C. to 126° C.

EXAMPLE 22

To a suspension of 31.6 g. of potassium permanganate in 300 ml. of watera solution of 12.7 g. of 2-allyl-phenol mesylester, 60 ml. of aceticacid and 1.35 g. of tetrabutyl ammoniumchloride in 300 ml. of methylenechloride is added with stirring, under cooling with ice-water. Thereaction mixture is stirred for 30 minutes with stirring, then 34 g. ofsodium hydrogensulphite and 60 ml. of a 1:1 mixture of hydrochloric acidand water are added. The methylene chloride phase is separated and theaqueous phase is shaken with two 100-ml. portions of methylene chloride.The methylene chloride solution is dried over sodium sulphate. Thecrystalline substance obtained after distilling off methylene chlorideis dissolved in 70 ml. of sodium hydrogencarbonate and the solutionobtained is shaken with methylene chloride. The aqueous solution isacidified with a 2 N aqueous hydrochloric acid solution. Theprecipitated crystals are filtered with suction and dried. Thus2-mesyloxy-phenylacetic acid is obtained, melting at 123° C. to 124° C.

EXAMPLE 23

To a suspension of 15.8 g. of potassium permanganate in 150 ml. of watera solution of 6 g. of 2-(1-methyl)-allyl-phenol-mesylester, 30 ml. ofacetic acid and 0.7 g. of tetrabutyl ammoniumchloride in 150 ml. ofbenzene is added with stirring, under cooling. Further on following theprocedure described in Example 22 filtering off the product obtainedwith suction 2-mesyloxy-hydratropic acid is prepared, melting at 94° C.to 96° C.

EXAMPLE 24

Following the procedure described in Example 22 but starting from 7.9 g.of 2-allyl-naphthol mesylester crystalline 1-mesyloxy-2-naphthyl-aceticacid is obtained, melting at 180° C. to 181° C.

EXAMPLE 25

Following the procedure described in Example 22 but replacing2-allyl-phenol mesylester by 8.54 g. of 2-tosyloxy-phenylacetic acid2-tosyloxy-phenylacetic acid is obtained, melting at 119° C. to 120° C.

EXAMPLE 26

To a suspension of 15.8 g. of potassium carbonate in 150 ml. of water6.8 g. of 2-allyl-4-methyl mesylester are added under ice-cooling, withstirring. Further on following the procedure described in Example 222-mesyloxy-5-methylphenylacetic acid is obtained as a white crystallinesubstance. Recrystallization from a 50% aqueous ethanol solution affordsa product melting at 101° C. to 102° C.

EXAMPLE 27

Following the procedure described in Example 22 but starting from 7.2 g.of 2-(1-methyl)-allyl-4-methyl-phenol mesylester2-mesyloxy-5-methyl-hydratropic acid is obtained in the form of whitecrystals, melting at 122° C. to 123° C.

EXAMPLE 28

To a suspension of 8.4 g. of potassium permanganate in 84 ml. of water asolution of 3.3 g. of 3-(1-methyl)-allyl-4-mesyloxy-benzophenone, 0.34g. of tetrabutyl ammoniumchloride and 31 ml. of acetic acid in 84 ml. ofbenzene is added with stirring. Then following the procedure describedin Example 22 a viscous substance is obtained, which is shaken withthree 20-ml. portions of ether. Upon addition of cyclohexyl amine thecyclohexyl amine salt of 2-mesyloxy-5-benzoyl-hydratropic acid isobtained as a white crystalline substance, melting at 151° C.

EXAMPLE 29

To a suspension of 57.12 g. of potassium permanganate in 542 ml. ofwater a solution of 24.58 g. of 2-methyl-6-(1-methyl)-allyl-phenolmesylester, 2.42 g. of tetrabutyl ammoniumchloride and 216 ml. of aceticacid in 542 ml. of benzene is added with stirring, under cooling withice-water. Further on following the procedure described in Example 222-mesyloxy-3-methyl-hydratropic acid precipitates as a white crystallinesubstance. The crystals are filtered off with suction. Melting point:138° C. to 142° C.

EXAMPLE 30

To a suspension of 25.6 g. of potassium permanganate in 250 ml. of watera solution of 9.2 g. of 3-allyl-4-mesyloxy-benzophenone, 1 g. oftetrabutyl ammoniumchloride and 90 ml. of acetic acid in 250 ml. ofbenzene is added at room temperature with stirring. Furtheron followingthe procedure described in Example 22 2-mesyloxy-5-benzoylphenylaceticacid is obtained as a white crystalline product. After filtering offwith suction and recrystallization from abs. ethanol the product meltsat 154° C. to 155° C.

EXAMPLE 31

To a suspension of 33.2 g. of potassium permanganate in 315 ml. of watera solution of 14.2 g. of 2-methyl-6-allyl-phenol mesylester, 126 ml. ofacetic acid and 1.4 g. of tetrabutyl ammoniumchloride in 315 ml. ofbenzene is added with stirring, under cooling with ice-water. Thenfollowing the procedure described in Example 222-mesyloxy-3-methyl-phenylacetic acid is obtained as a white crystallineproduct, melting at 121° C. to 124° C.

EXAMPLE 32

6.85 g. of 2-(1-methyl-allyl)-4-phenoxy phenylmesylester are dissolvedin 180 ml. of benzene containing 0.73 g. of tetrabutyl ammoniumchlorideand 67 ml. of glacial acetic acid. The solution obtained is added to asolution of 19 g. of potassium permanganate in 180 ml. of water withstirring. Then following the procedure described in Example 22 a slowlysolidifying oily product is obtained. Melting point of the crystallineproduct obtained after standing amounts to 113° C. to 118° C. Afterrecrystallization from 30 ml. of diisopropyl ether the melting point of2-mesyloxy-5-phenoxyhydratropic acid is 123° C. to 125° C.

EXAMPLE 33

1.53 g. of 2-allyl-4-phenoxy phenylmesylester are dissolved in 47 ml. ofbenzene containing 0.2 g. of tetrabutyl ammoniumchloride and 17 ml. ofglacial acetic acid. The solution obtained in poured into a solution of5 g. of potassium permanganate in 47 ml. of water. Then following theprocedure described in Example 22 an oily product is obtained, which isdissolved in a 1 N solution of sodium hydrogencarbonate. The solutionobtained is shaken with two 10-ml. portions of benzene, whereupon thealkaline phase is acidified with a concentrated hydrochloric acidsolution and shaken with three 10-ml. portions of ether. The combinedethereal extracts are dried and evaporated to give 2-mesyloxy-5-phenoxyphenylacetic acid, melting at 121° C.

EXAMPLE 34

To a solution of 33 g. of 2-methane-sulphonyloxy-3-phenoxy-hydratropicacid in 200 ml. of methanol 28 ml. of triethyl amine and 2 g. of a 5%palladium on charcoal catalyst are added at 25° C. The mixture is thenhydrogenated under atmospheric pressure until a calculated amount ofhydrogen is used up. The catalyst is filtered off and the solution isevaporated. The evaporation residue is taken up in water, acidified witha 20% aqueous hydrochloric acid solution and the separated oil isextracted with chloroform. The chloroform solution is evaporated afterdrying over sodium sulphate, and the residue is distilled off. 23 g.(95%) of 3-phenoxy-hydratropic acid are obtained, boiling at 190° C. to192° C. (0.4 mmHg.). n_(D) ²⁵ =1.5751. Melting point of thecorresponding cyclohexylamine salt amounts to 153° C. to 154° C.

EXAMPLE 35

Following the procedure described in Example 34 but starting from

32.5 g. of 2-(1-methane-sulphonyloxy-6-methoxy-2-napthyl)-propionicacid,

34 g. of 2-methanesulfphonyloxy-4-phenyl-5-fluoro-hydratropic acid,

35 g. of 2-methanesulphonyloxy-5-benzoyl-hydratropic acid and

24.5 g. of 1-methane-sulphonyloxy-2-naphthyl-acetic acid, respectivelythe following end products are obtained:

    ______________________________________                                                                 melting point                                        End product              (°C.)                                         ______________________________________                                        22   g. of 2-(6-methoxy-2-naphthyl)-propionic                                        acid                  153 to 155                                       23.3 g. of 3-fluoro-4-phenyl-hydratropic                                             acid                  110 to 111                                       24.4 g. of 3-benzoyl-hydratropic acid                                                                       90 to 92 and                                    16   g. of 2-naphthyl-acetic acid                                                                          141 to 142, resp.                                ______________________________________                                    

EXAMPLE 36

To a solution of 77.5 g. of 2-methane-sulphonyloxy-4-methyl-hydratropicacid in 600 ml. of methanol 84 ml. of triethyl amine and 6 g. of a 5%palladium on charcoal catalyst are obtained, and the mixture ishydrogenated at 25° C. until a calculated amount of hydrogen is used up.Catalyst is filtered off and the filtrate is evaporated. The residue istaken up in water and the solution is acidified with a 20% aqueoushydrochloric acid solution. The separated 4-methyl-hydratropic acid isextracted with chloroform and the chloroform extract is dried oversodium sulphate. Evaporation of the solution affords4-methyl-hydratropic acid.

EXAMPLE 37

To a solution of 24.5 g. of 2-methane-sulphonyloxy-hydratropic acid in200 ml. of methanol 28 ml. of triethyl amine and 2 g. of a 5%palladium-on-charcoal catalyst are added. The mixture is hydrogenated at25° C., under atmospheric pressure until a calculated amount of hydrogenis used up. The catalyst is filtered off and the filtrate is evaporated.The residue is taken up in water and acidified with a 20% aqueoushydrochloric acid solution. The separated hydratropic acid is extractedwith chloroform. The chloroform solution is dried over sodium sulphate,evaporated and the residue is distilled off. 13.5 g. (90%) ofhydratropic acid are obtained, boiling at 145° C. (13 mmHg.); n_(D) ²⁵=1.5219.

EXAMPLE 38

To a solution of 4.1 g. of 2-toluene-sulphonyloxy-3-phenoxy-hydratropicacid in 150 ml. of alcohol 24 g. of a W-6 nickel catalyst are added, andthe mixture is hydrogenated at 25° C., under atmospheric pressure untila calculated amount of hydrogen is used up. The catalyst is filteredoff, the filtrate is evaporated and the residue is taken up in water andacidified with a 10% aqueous hydrochloric acid solution. The separatedoil is extracted with chloroform, the chloroform solution is dried oversodium sulphate and evaporated. 2.1 g. (89%) of 3-phenoxy-hydratropicacid are obtained. Melting point of the corresponding cyclohexylaminesalt amounts to 151° C. to 153° C.

EXAMPLE 39

To a solution ofm 3.3 g. of 2-toluene-sulphonyloxy-4-methyl-hydratropicacid in 150 ml. of alcohol 15 g. of Raney nickel are added as a catalystand the reaction mixture is boiled for three hours with stirring. Uponcooling the catalyst is filtered off and the filtrate is evaporated. Theresidue is triturated with 50 ml. of water and the separated product isextracted with chloroform. Evaporation of the chloroform extract affords1.5 g. (91%) of 4-methyl-hydratropic acid.

EXAMPLE 40

To a solution of 3.4 g. of 2-amino-sulphonyloxy-3-phenoxy-hydratropicacid in 20 ml. of methanol 2.8 ml. of triethylamine and 0.2 g. of a 5%palladium-on-charcoal catalyst are added. The mixture is hydrogenated at25° C., under atmospheric pressure until a calculated amount of hydrogenis used up. The catalyst is filtered off and the filtrate is evaporated.The evaporation residue is taken up in water, acidified with a 20%aqueous hydrochloric acid solution and the separated oil is extractedwith chloroform. The chloroform extract is dried over sodium sulphateand is evaporated to give 2.2 g. (91%) of 3-phenoxy-hydratropic acid.Melting point of the corresponding cyclohexylamine salt amounts to 151°C. to 153° C.

EXAMPLE 41

Following the procedure described in Example 40 but starting from

4.5 g. of 2-(N-benzoylamino-sulphonyloxy)-5-benzoylhydratropic acid;

3.8 g. of2-[1-(N-methoxy-carbonylamido-sulphonyloxy)-6-methoxy-2-naphthyl]-propionicacid and

2.44 g. of 2-mesyloxy-3-methyl-phenylacetic acid, respectively thefollowing end products are obtained:

    ______________________________________                                                                 Melting point                                        End product              (°C.)                                         ______________________________________                                        2.35 g. of 2-benzoyl-hydratropic acid                                                                       90 to 92                                        2.2  g. of 2-(6-methoxy-2-naphthyl)-propionic                                        acid                  153 to 155                                            3-methyl-phenylacetic acid                                                                             67 to 69, resp.                                 ______________________________________                                    

EXAMPLE 42

To a solution of 4.2 g. of 2-hydroxy-3-phenoxy-hydratropic acid sulphatedipotassium salt in 50 ml. of water 2 g. of potassium hydroxide and 2 g.of a Raney nickel catalyst prepared freshly according to Urushibara, andthe reaction mixture is stirred at 60° C. for 10 to 15 minutes. Thecatalyst is filtered off and the filtrate is acidified with a 20%aqueous hydrochloric acid solution. The separated solution is extractedwith chloroform and the chloroform solution is dried over sodiumsulphate and evaporated. 2.35 g. (97%) of 3-phenoxy-hydratropic acid areobtained. Melting point of the corresponding cyclohexylamine salt: 151°C. to 153° C.

EXAMPLE 43

To a solution of 3.4 g. of 2-hydroxy-4-methyl-hydratropic acid sulphatedipotassium salt in 50 ml. of water Raney nickel is added as a catalyst,and the mixture is hydrogenated until the calculated amount of hydrogenis used up. The catalyst is filtered off and the filtrate is acidifiedwith a 20% aqueous hydrochloric acid solution. The separated oil isextracted with chloroform. Evaporation of the chloroform extract affords1.5 g. (91.5%) of 4-methyl-hydratropic acid.

EXAMPLE 44

3.8 g. of 2-N,N'-dicyclohexyl-isocarbamido)-4-methyl-hydratropic acidare dissolved in isopropanol and to the solution obtained 0.2 g. of a 5%palladium-on-charcoal catalyst are added. The mixture is thenhydrogenated at 25° C., under atmospheric pressure until the calculatedamount of hydrogen is used up. Catalyst is filtered off and the filtrateis evaporated. The residue is treated with a 5% sodium carbonatesolution and is filtered. The filtrate is acidified with a 20% aqueoushydrochloric acid solution and the separated oil is extracted withchloroform. The chloroform extract is dried over sodium sulphate, driedand evaporated. 1.4 g. (85%) of 4-methyl-hydratropic acid are obtained.

EXAMPLE 45

3 g. of 2-hydroxy-4-methyl-hydratropic acid phenylurethane are dissolvedin acetic acid. To the solution 0.4 g. of a 5% palladium-on-charcoalcatalyst are added, and the mixture is hydrogenated at 25° C. until thecalculated amount of hydrogen is used up. The catalyst is filtered offand the filtrate is evaporated. The residue is admixed with a 10%aqueous hydrochloric acid solution and the separated oil is extractedwith chloroform. The chloroform solution is dried over sodium sulphateand evaporated. 1.1 g. (67%) of 4-methyl-hydratropic acid are obtained.

EXAMPLE 46

3.2 g. of[5-methyl-2-(1-carboxy-1-ethyl)-phenyl]-(1-phenyl)-5-tetrazolyl etherare dissolved in 100 ml. of benzene and to the solution obtained 0.8 g.of a 5% palladium-on-charcoal catalyst are added. The mixture ishydrogenated at 35° to 40° C., under a pressure of 2.8 atm., until thecalculated amount of hydrogen is used up. The catalyst is filtered offand washed with hot ethanol. The filtrate is evaporated and the residueis treated with a 5% aqueous sodium carbonate solution. After filtrationthe filtrate is acidified with a 20% aqueous hydrochloric acid solutionand the separated oil is extracted with chloroform. The chloroformsolution is dried over sodium sulphate and evaporated. 1.4 g. (85%) of4-methyl-hydratropic acid are obtained.

EXAMPLE 47

To a solution of 1.29 g. of 2-mesyloxy-5-methyl-hydratropic acid in 25ml. of methanol 1.4 ml. of triethylamine and 0.2 g. of a 5%palladium-on-charcoal catalyst are added. The mixture is hydrogenated at25° C., under atmospheric pressure until the calculated amount ofhydrogen is used up. The catalyst is filtered off and the solution isevaporated. The evaporation residue is taken up in water, acidified witha 20% aqueous hydrochloric acid solution and shaken with ether. Ether isdistilled off to give 3-methyl-hydratropic acid as an oily residue. Thecorresponding cyclohexylamine salt melts at 168° C. to 169° C.

EXAMPLE 48

1.22 g. of 2-mesyloxy-5-methyl-phenylacetic acid are dissolved in 20 ml.of methanol and to the solution obtained 1.4 ml. of triethyl amine and0.2 g. of a 5% palladium-on-charcoal catalyst are added. Then followingthe procedure described in Example 47 a white, crystalline product isobtained, melting at 64° C. to 65° C. The product obtained is5-methyl-phenylacetic acid.

What we claim is:
 1. A compound of the formula: ##STR18## wherein R¹ ishydrogen, methyl or ethyl;R² is hydrogen, fluoro or alkyl having 1 to 4carbon atoms; R³ is hydrogen, phenyl, alkoxy having 1 to 6 carbon atoms,phenoxy, thenoyl or benzoyl; or R² and R³ together with the phenyl groupto which they are attached form a naphthyl group which is unsubstitutedor substituted by C₁ to C₄ alkyl or C₁ to C₄ alkoxy; R¹⁰ isphenylaminocarbonyl, 1-phenyl-5-tetrazolyl, a group --SO₂ Me, wherein Meis a metal atom selected from the group which consists of sodium andpotassium, or a group --SO₂ --R⁶, in which R⁶ is alkyl having 1 to 4carbon atoms, 4-methylphenyl, amino, C₁ to C₄ alkoxycarbonylamino,benzoylamino or a group R⁷ ##STR19## in which R⁷ is cycloalkyl having 5or 6 carbon atoms; and R is carboxyl.
 2. The compound defined in claim 1selected from the group consisting of:2-mesyloxy-phenyl-acetic acid;2-mesyloxy-hydratropic acid; 1-mesyloxy-2-naphthyl-acetic acid;2-tosyloxy-phenylacetic acid; 2-mesyloxy-5-methyl-hydratropic acid;2-mesyloxy-5-benzoyl-hydratropic acid; 2-mesyloxy-3-methyl-hydratropicacid; 2-mesyloxy-5-benzoyl-phenyl acetic acid;2-mesyloxy-3-methyl-phenyl acetic acid; 2-mesyloxy-5-phenoxy-hydratropicacid; 2-mesyloxy-5-phenoxy-phenylacetic acid;2-mesyloxy-3-phenoxy-hydratropic acid;2-(1-mesyloxy-6-methoxy-2-naphthyl)-propionic acid;2-mesyloxy-4-phenyl-5-fluoro-hydratropic acid;2-mesyloxy-4-methyl-hydratropic acid; 2-tosyloxy-3-phenoxy-hydratropicacid; 2-tosyloxy-4-methyl-hydratropic acid;2-amino-sulphonyloxy-3-phenoxy-hydratropic acid;2-(N-benzoylamino-sulphonyloxy)-5-benzoyl-hydratropic acid;2-(N,N'-dicyclohhexyl-isocarbamido)-4-methyl-hydratropic acid;2-hydroxy-4-methyl-hydratropic acid-phenyl urethane; and[5-methyl-2-(1-carboxy-1-ethyl)-phenyl]-(1-phenyl)-5-tetrazolyl ether.3. 2-(N,N'-dicyclohexyl-isocarbamido)-4-methyl-hydratropic acid.